Cystic fibrosis (CF) is the most common life-shortening genetic disease in Europe and North America. It is caused by inheritance of two mutant alleles of the CFTR (cystic fibrosis transmembrane regulator) gene and results in altered ion transport across epithelial membranes and altered cytokine regulation in the lungs. Persons with CF can experience variable GI disorders that can be managed with nutritional and digestive enzyme supplementation and develop thick mucus in the lungs that impairs mucocilliary transport and impairs the host ability to clear inhaled bacteria. Greater than 90% of deaths in persons with CF in 2003 could be directly or indirectly linked to loss of lung function resulting from cycles of pulmonary obstruction, bacterial infection, and local inflammation (CFF National Patient Registry).
Two commercial therapies have been developed and registered in the US and Europe to combat the thick mucus and chronic bacterial infections that lead to lung function decline in CF: dornase alpha (rhDNase) (Pulmozyme®), and tobramycin inhalation solution (TOBI®). Both products were shown to be effective in persons with CF in prospective, randomized, blinded, placebo controlled clinical studies that compared change in pulmonary function (as FEV1% predicted) from baseline relative to placebo. Pivotal efficacy trials for both products were conducted in subjects with moderate to severe lung disease (FEV1 between 25% and 75% of predicted values based on height, age, and sex). Change in pulmonary function is considered a valid surrogate for survival as a clinical study endpoint in CF because of the high incidence of death as a result of loss of lung function in CF, and demonstration that pulmonary function is a strong independent predictor of relative survival for persons with CF. Change in pulmonary function has several significant short-comings as an endpoint for demonstration of clinical efficacy.
Pulmonary function testing has a high degree of variability, and pulmonary functions of individuals vary sufficiently over time. It is not unusual to observe population standard deviations of 15% to 20% of predicted FEV1. Large standard deviations of measured means require the use of large population samples in order to accurately estimate true mean differences in treatment response between study arms (FIG. 1).
Individuals with CF do not experience uniform rates of pulmonary function loss throughout disease progression, and there can be significant variability in underlying CF disease severity (and thus rate of lung function loss) between individuals. The result is that substantial changes in lung function in individuals during clinical trials can be diluted by modest changes in subjects with less severe disease. The net result of testing “mixed” populations is a reduced observed treatment effect. As observed differences in treatment outcomes decrease between study arms, sample sizes required to prove that observed differences are clinically significant increase (FIG. 1).
Pulmonary function testing requires training and cooperation, and for this reason it is not considered a reliable measure prior to 6 years of age.
Considerable effort has been focused on the development of agents intended to reverse the primary CF defect, thereby providing a “cure” for CF. A variety of approaches are under investigation, including improving the processing of mutant CFTR proteins, providing functional CFTR by gene therapy, and changing the function of alternative epithelial ion channels. Because these therapies are intended to reverse the underlying CF defect, rather than to mitigate downstream biological consequences of the defect, they would ideally be chronic therapies that would be administered before significant disease progression has occurred. This creates a significant challenge for developers of such therapies, in that the current accepted endpoint of change in pulmonary function is employed at the lowest risk and expense after significant disease progression has occurred. Demonstrating the safety and efficacy of a therapy administered before disease progression has occurred would require that a blinded placebo control population develop measurable lung disease. Such a study would require several hundred subjects per arm and duration of years to allow for measurable disease progression.
Nasal potential difference (NPD) is a relatively non-invasive measure that can be collected in infants, but that lacks key features of a viable endpoint for approval. NPD is directly linked to ion movement across the epithelium, and a change in NPD can be used to demonstrate therapeutic mitigation of the CF defect (Konstan et al., Hum. Gene Ther. (2004) 15(12):1255-69). A variation of NPD has recently been proposed in which potential differences are measured in bronchoscopic biopsies of distal airways in young children (Davies et al., Am. J. Respir Crit. Care Med., 176:1015-9 (2005)). Unfortunately, the magnitude to which an individual's potential difference deviates from a normal value does not appear to be particularly predictive of the ultimate severity of their CF lung disease progression (Fajac et al., Thorax. (2004) 59(11): 971-6), and there is no algorithm for correlating change in potential difference to change in disease progression.
High-resolution computerized tomography (HRCT) has been proposed as a method to obtain data on lung disease progression in infants and prior to significant disease progression (Marchant et al., Pediatr. Pulmonol. (2001) 31(1):24-9; Brody et al., J. Pediatr. (2004) 145(1):32-8). HRCT of the lung has the advantages that it can be performed in younger subjects and can identify anatomical events that ultimately lead to loss of pulmonary function, but HRCT does not overcome a basic limitation of lung function as an endpoint: there is substantial variability in the measure, and lung disease does not develop predictably early in the life of an infant with CF. In addition, there is no data set with which a clinician (or regulator) can extrapolate from an early change in HRCT global scoring over time to a risk of CF disease progression or survival, and serial HRCT in infants is not without risk due to cumulative radiation exposure.
Given the challenges with effect on pulmonary function as an efficacy endpoint for regulatory approval of a curative CF therapy, an alternative clinical endpoint more directly related to the primary CF defect is needed. In addition to being measurable in infants with CF, the clinical endpoint ideally also should be methodologically tractable (in that the measure employed is relatively unambiguous and reproducible within and between subjects), statistically robust (where differences in incidence and/or magnitude of the measure between persons with CF and persons without CF can be demonstrated using relatively modest sample sizes), clinically valid (in that clinicians would consider a statistically significant change in the incidence or magnitude of the measure as clinically meaningful with respect to risk of disease progression), and mechanistically sound (in that the measured endpoint can in some way be linked back to the primary defect). The invention addresses these challenges.
The invention takes advantage of previous observations that persons with CF are prone to lung infections with pathogens such as Pseudomonas aeruginosa, Staphylococcus aureus, and Stenotrophomonas maltophilia at an early age. In 2003, ˜50% of persons with CF in the US under age 2 years were reported to have S. aureus infections (CFF National Patient Registry), and ˜30% were reported to have P. aeruginosa infections. It is believed that these opportunistic infections are a result of thickened mucus and loss of mucocilliary transport caused by the primary CF defect.